Association of BRCA Mutations and BRCAness Status With Anticancer Drug Sensitivities in Triple-Negative Breast Cancer Cell Lines

Teraoka, Saeko; Muguruma, Masako; Takano, Naoharu; Miyahara, Kana; Kawate, Takahiko; Kojima, Hiroshi; Yamada, Kimito; Miyazawa, Kenji; Ishikawa, Takashi

doi:10.1016/j.jss.2019.12.040

Cited by 8 publications

(8 citation statements)

References 33 publications

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“…However, their MGMT deficiency and response to TMZ predisposes these subtypes for TMZ combination with [ 125 I]-PARPi-01 treatment [ 33 , 54 ]. Among the above mentioned cell lines the BRCAness signature has been reported to be low for BT20 and MDA-MB-231, which have still shown promising response to Auger emitter-based therapy [ 55 ]. Other Basal B non-responsive TNBC cell lines include SUM149PT and SUM1315M02.…”

Section: Discussionmentioning

confidence: 99%

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study

Sankaranarayanan

Peil

Vogg

et al. 2022

Cancers

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PARP1 inhibitors (PARPi) are currently approved for BRCAmut metastatic breast cancer, but they have shown limited response in triple negative breast cancer (TNBC) patients. Combination of an Auger emitter with PARPis enables PARP inhibition and DNA strand break induction simultaneously. This will enhance cytotoxicity and additionally allow a theranostic approach. This study presents the radiosynthesis of the Auger emitter [125I] coupled olaparib derivative: [125I]-PARPi-01, and its therapeutic evaluation in a panel of TNBC cell lines. Specificity was tested by a blocking assay. DNA strand break induction was analysed by γH2AX immunofluorescence staining. Cell cycle analysis and apoptosis assays were studied using flow cytometry in TNBC cell lines (BRCAwt/mut). Anchorage independent growth potential was evaluated using soft agar assay. [125I]-PARPi-01 showed PARP1-specificity and higher cytotoxicity than olaparib in TNBC cell lines irrespective of BRCA their status. Cell lines harbouring DNA repair deficiency showed response to [125I]-PARPi-01 monotherapy. Combined treatment with Dox-NP further enhanced therapeutic efficiency in metastatic resistant BRCAwt cell lines. The clonogenic survival was significantly reduced after treatment with [125I]-PARPi-01 in all TNBC lines investigated. Therapeutic efficacy was further enhanced after combined treatment with chemotherapeutics. [125I]-PARPi-01 is a promising radiotherapeutic agent for low radiation dosages, and mono/combined therapies of TNBC.

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Section: Discussionmentioning

confidence: 99%

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study

Sankaranarayanan

Peil

Vogg

et al. 2022

Cancers

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“…Authors concluded that BRCAness may suggest resistance to taxane-based CT [134]. Similarly, in the just above-mentioned study [133] the 50% inhibitory concentration of docetaxel was higher in BRCA mutant and BRCAness cell lines than their counterparts. BRCA1-like scores showed a weak positive correlation with docetaxel sensitivity (r = 0.377; p = 0.039).…”

Section: Brcanessmentioning

confidence: 80%

“…An inverse correlation was found between BRCA1-like scores and cisplatin sensitivity (r = −0.407; p = 0.013) and BRCA1 gene knockdown increased the cisplatin sensitivity of Michigan Cancer Foundation-7 cells. Authors concluded that BRCA1-like scores were associated with cisplatin sensitivity [133].…”

Section: Biomarkers Predicting Resistance To Platinum-based Therapymentioning

confidence: 99%

Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC

Scatena

Ghilli

Bargagna

et al. 2022

IJMS

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Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance.

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“…Dysregulation of the DNA damage repair process is vital in drug sensitivity, including genotoxic agents or DNA-damaging anticancer drugs 43 . Therefore, we explored the effects of TAB182 on drug sensitivity in the MDA-MB-231 and BT549 cell lines, which are the BRCA-wild type TNBC cells, compared to BRCA-mutated cells, exhibiting intrinsic resistance to Olaparib or Cisplatin 44,45 . Our study indicates that the overexpression of TAB182 increased the inhibitory effects of Olaparib or Cisplatin on cell viability more than any treatment alone, which reveals that TAB182 expression negatively regulates the therapeutic resistance in TNBC cells.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of TAB182 promotes cancer stem-like cell properties and therapeutic resistance in triple-negative breast cancer cells

Wang

Zhang

et al. 2023

Preprint

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Table 182 participates in DNA damage repair and radio-/chemo-sensitivity regulation in various tumors, but its role in tumorigenesis and therapeutic resistance of breast cancer remains unclear. In the current paper, we observed that Triple-Negative Breast Cancer (TNBC), a highly aggressive type of breast cancer, exhibits a lower expression of TAB182. TAB182 knockdown stimulates cell proliferation, migration, and invasion in TNBC cells. Our study first constructed the RNA-seq data to explore the cellular functions of TAB182 at the genome level in TNBC cells. Transcriptome analysis and in vitro experiments identify that TAB182 downregulation drives the enhanced properties of cancer stem-like cells (CSCs) in TNBC cells. Furthermore, TAB182 deletion contributes to the resistance of cells to Olaparib or Cisplatin, which could be rescued by silencing GLI2, a downstream gene of cancer stemness-related signaling pathways. Our results reveal a novel function of TAB182 as a significant negative regulator of cancer stem-like properties and drug sensitivity in TNBC cells, suggesting TAB182 may be a tumor suppressor gene and associated with more therapeutic benefits for TNBC.

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Association of BRCA Mutations and BRCAness Status With Anticancer Drug Sensitivities in Triple-Negative Breast Cancer Cell Lines

Cited by 8 publications

References 33 publications

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study

Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC

Downregulation of TAB182 promotes cancer stem-like cell properties and therapeutic resistance in triple-negative breast cancer cells

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